Taming the Beast: Diarrhea
Juliet Sio Aguilar, M.D., M.Sc.(Birm)
Professor of Pediatrics
University of the Philippines Manila
Active Consultant, St. Luke’s Medical Center
• “Glocal” Burden
• Local Epidemiology
• Diagnostic Decisions
• Treatment Options
• Preventive Strategies
Outline: Taming Killer Diarrhea
Global Burden of Diarrhea
Black RE et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 2010; 375: 1969-87.
Global Deaths from Diarrhea
Black RE et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 2010; 375: 1969-87.
11.3% of
total
deaths in
children
1-59 mos
Every year
~5000 diarrheal deaths
Everyday
~13 young children dying
Local Burden of Diarrhea
Black RE et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 2010; 375: 1969-87.
World Health Organization. Mortality Country Fact Sheet 2006..
• Underlying cause of under-5 mortality
(WHO estimates, 2000-2003)
• 53% of ALL deaths
• 61% of deaths due to diarrhea globally
• 80% of children with diarrhea die during
the first 2 years of life
Malnutrition and
Diarrheal Diseases
Bryce J, Boschi-Pinto C, Shibuya K, Black RE, WHO Child Health Epidemiology Reference Group.
WHO estimates of the causes of death in children. Lancet 2005: 365:1147-52.
DOH. Field Health Service Information System Annual Report 2007.
DOH. Field Health Service Information System Annual Report 2007.
3-28% of all
diarrheal
episodes
(de Andrade and
Fagundes-Neto, 2011)
Highest
incidence in
the 1st 2 years
of life
• 10% of acute diarrhea
cases in Philippines
become persistent
(Santos Ocampo et al, 1988)
• Highest prevalence in the
1st year of life with 63% of
cases (Santos Ocampo et al, 1988)
(Black, 1993)
Persistent Diarrhea
Most Common Microorganisms Reported for Acute Endemic
Diarrhea among U5 Children in Developing World
All Episodes
< 2 years
Rotavirus
EPEC,ETEC
Astrovirus, Caliciviruses, enteric Adenovirus
Shigella flexneri, Shigella dysnteriae type 1
Campylobacter jejuni
ETEC, EAEC
2-5 years
ETEC
S. flexneri, S. dysenteriae type 1
Rotavirus
Non-typhi Salmonella
Giardia lamblia
Watery Mucous
< 2 years
Rotavirus
EPEC,ETEC
Astrovirus, Caliciviruses, enteric Adenovirus
Shigella flexneri, Shigella dysnteriae type 1
Campylobacter jejuni
ETEC,EAEC
2-5 years
ETEC
Shigella flexneri, Shigella dysenteriae type
Rotavirus
O’Ryan M, Prado V, Pickering LK.Semin Pediatr Infect Dis 2005; 16: 125-36.
Burden of Rotavirus Disease
(Global RV Surveillance Network)
Rotavirus Surveillance – Worldwide, 2009. MMWR 2011; 60(16): 514-6.
Etiologic Agents of Acute Diarrhea
in selected Philippine Hospitals
Paje-Villar et al,. PJP 1993; 42: 1-24. Adkins HJ et al. J Clin Microbio 1987; 25: 1143-7. San Pedro MC, Walz SE. SEAJTMPH 1991; 22: 203-10.
%
Prevalence of Rotavirus Disease
Carlos C et al. J Infect Dis 2009; 200 (Suppl 1): S174-81.
Bacteria
E. coli (EAEC;
EPEC)
Campylobacter spp
S. enteritidis
Shigella spp
C. difficile
Klebsiella spp
Protozoa
G. lamblia
B. hominis*
Cryptosporidium spp*
E. histolytica
Cyclospora
cayetanensis*
Microsporidium spp*
Viruses
Astrovirus
Enteroviruses
Picornaviruses
*particularly
associated with HIV
Etiologic Agents for Persistent Diarrhea
De Andrade JA , Fagundo-Neto U. J Pediatr (Rio J) 2011; 87: 188-205.
• Diagnosis for most cases of acute diarrhea: clinical
• Based on the clinical syndromes
• Acute watery diarrhea
• Bloody diarrhea
• Persistent diarrhea
• Diarrhea with severe malnutrition
• Routine stool examination not necessary in most
cases of acute watery diarrhea
• Stool microscopy and culture indicated only when
patients do not respond to fluid replacement,
continued feeding, and zinc supplementation
Diagnostic Investigations
• Ascertain if due to an infection
• 40-60% due to shigellosis
• Empiric treatment with ciprofloxacin
15 mg/kg/dose BID for 3 days
• Consider differential diagnosis
• Anal fissure
• Intussusception
• Allergic colitis
Bloody Diarrhea
• Diagnosis made on clinical grounds (onset
and duration of diarrhea)
• Most of the cases (> 60%) due to:
• Acute intestinal infection
• Dietary intolerance
• Protein-sensitive enteropathy (cow’s milk)
• Secondary disaccharide malabsorption
(lactose)
• In 30% of cases, no etiologies can be
established despite extensive investigations.
Persistent Diarrhea
Bhutta et al. JPGN 2004; 39: S711-16.
Mainstays in Diarrhea
Management
• Malnutrition underlie 61% of
diarrheal deaths globally.
• Micronutrient deficiencies
•
•
•
•
Diminish immune function
Increase susceptibility to infections
Predispose to severe illnesses
Prolong duration of illness
Micronutrient Supplementation in
Diarrheal Disease
• Early studies: single nutrients
• To combat diarrhea, respiratory infections,
and anemia
• To improve child growth and development
• Recent studies: multiple nutrients
• Increasing recognition that micronutrient
deficiencies do not occur in isolation
• Multiple MNS may be more cost-effective
Single vs. Multiple Nutrient
Supplementation (MNS)
Ramakrishnan U, Goldenberg T, Allen LH. Do multiple micronutrient interventions improve child health,
growth, and development? J Nutr 2011; 141: 2066-75.
Therapeutic Strategy
• Zinc
• Vitamin A
• Folic acid
Preventive Strategy
• Zinc
• Vitamin A
• Multiple
micronutrients
Single vs. Multiple
Nutrient Supplementation
Acute Diarrhea
• Reduction in duration
of -0.69 day
[95%CI: -0.97 to -0.40]
• Reduction in diarrhea
risk lasting >7 days
RR=0.71 [95% CI: 0.530.96]
• No reduction in stool
output
• Based on 18 RCTs
(n=11,180 mainly from
developing countries)
Persistent Diarrhea
• Zinc (with MV vs MV
alone; singly or with
vitamin A) significantly
• Reduced stool output
• Prevented weight loss /
promoted weight gain
• Promoted earlier clinical
recovery
• Based on 2 RDBCTs in
mod malnourished
children 6-24 mos
(n=190 + 96)
Zinc Supplementation: Treatment
Patro B, Golicki D, Szajewska H. Aliment Pharmacol Ther 2008; 28: 713-23.
Roy SK et al. Acta Paediatr 1998; 87: 1235-9.
Khatun UH, Malek MA, Black RE….Roy SK. Acta Paediatr 2001; 90: 376-80.
1990s
2000s
• Continuous trials (1-2
RDAs 5-7 times/week)
• OR= 0.82 [95%CI: 0.72, 0.93]
incidence
• OR = 0.75 [95%CI: 0.63, 0.88]
prevalence
• Short-course trials (2-4
RDAs daily for 2 wks)
• OR = 0.89 [95%CI: 0.62, 1.28]
incidence
• OR = 0.66 [95%CI: 0.52, 0.83]
prevalence
• 9% reduction in incidence
of diarrhea
• 19% reduction in
prevalence of diarrhea
• 28% reduction in multiple
(>2) diarrheal episodes
• No statistically significant
impact on persistent
diarrhea, dysentery or
mortality
Zinc Supplementation: Prevention
Bhutta A, Black RE, Brown KH et al. J Pediatr 1999; 135: 689-97.
Patel AB, Mamtani M, Badhoniya N, Kulkarni H. BMC Infect Dis 2011; 11: 122.
• Decline in protective efficacy due to
variability in:
• Microbial isolates
• Klebsiella sp most responsive; E coli neutral;
rotavirus worse outcome
• Age
• Less efficacious in infants <12 mos
• More pathogens in those <12 mos which are
refractory to zinc (e.g., rotavirus)
• Zinc salts used
• Zinc gluconate with most significant reduction in
incidence in comparison to zinc sulfate and zinc
acetate
Zinc Supplementation: Prevention
Patel AB, Mamtani M, Badhoniya N, Kulkarni H. BMC Infect Dis 2011; 11: 122.
• Inconsistent results as treatment adjunct
• Beneficial only as prophylactic strategy
Meta-analysis of 43 trials (215,633 aged 6m-5y)
• Reduction in mortality from diarrhea
RR=0.78 [95% CI: 0.57, 0.91]
• Reduction in diarrhea incidence
RR=0.85 [95% CI: 0.82, 0.87]
• No significant effect on hospitalizations due to diarrhea
• Increased vomiting within 48 hrs of supplementation
RR=2.75 [95% CI: 1.81, 4.19]
• Can ameliorate adverse effect of stunting
associated with persistent diarrhea
Vitamin A Supplementation
Fischer Walker CL, Black RE. Micronutriennts and diarrheal disease. Clin Infect Dis 2007; 45:S73-7.
Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. BMJ 2011; 343: d5094 doi: 10.1136.
Villamor E et al. Pediatr 2002; 109 (1).
• RDBPCT on clinical efficacy of combination
therapy vs. monotherapy among 6-24 mos with
acute diarrhea (n=167) vs. control
• Supplementation of zinc, zinc + vitamin A, and zinc +
micronutrients (vitamin A + Fe, Cu, Se, B12, folate) vs.
control
• Comparable outcomes for supplemented groups with
regards to duration, volume of diarrhea, and
consumption of oral rehydration solution
Vitamin A or MMN with zinc does not cause further
reduction in diarrhea outcomes, confirming the clinical
benefit of zinc alone in the treatment of diarrhea.
MMN Supplementation: Treatment
Dutta P, Mitra U, Dutta S et al. J Pediatr 2011; 159: 633-7.
• Most studies in diarrhea prevention
• No benefit in Peru, Indonesia, South Africa
• South Africa
• Lower diarrhea incidence only among stunted
children when compared with vitamin A alone
• Vitamin A + zinc
RR=0.52 [95% CI: 0.45, 0.60]
• MMN (with vit A, zinc)
RR=0.57 [95% CI: 0.49, 0.67]
MMN does not lower incidence of diarrhea except among
stunted children when used with supplemental zinc.
MMN Supplementation: Prevention
Lopez de Romana G et al. J Nutr 2005; 135: S646-52.
Untoro J et al. J Nutr 135; S639-45.
Luabeya KA et al. Plos One June 2007 (6): e541
Chhagan MK et al. Eur J Clin Nutr 2009; 63: 850-7.
Acute Diarrhea
Persistent Diarrhea
• Reduction in duration
of diarrhea by 24.76
hrs [95% CI: 15.933.6 hrs]
• Decrease risk for
diarrhea lasting > 4
days with
risk ratio 0.41
[95% CI: 0.32-0.53]
• Small review of 464
subjects
• Reduction in duration
of diarrhea by 4.02
days [95% CI: 4.613.43]
• Decrease in stool
frequency
Adjuncts in Treatment: Probiotics
Allen SJ, Martinez EG, Gregorio GV, Dans LF. Cochrane Database Syst Rev 2010 Nov 10; (11): CD003048.
Bernaola Aponte G et al.. Cochrane Database Syst Rev 2010 Nov 10; (11): CD007401.
• Individual patient data meta-analysis
• 9 RCTs (n=1384)
• Higher proportion of recovered patients in
racecadotril group vs placebo
• Hazard ratio = 2.04 [95% CI: 1.85-2.32] p<0.001
• Ratio of stool output between
racecadotril/placebo
• = 0.59 [0.51-0.74] p<0.001
• Ratio of mean number of diarrheic stools
between racecadotril/placebo
• = 0.63 [0.51-0.74] p<0.001
Racecadotril in Diarrhea
Lehert P, Cheron G, Calatayud GA, Cezard JP et al. Racecadotril for childhood gastroenteritis:
an individual patient data meta-analysis. Dig Liver Dis 2011; 44: 707-13.
• Breast feeding
• Improved weaning
practices
• Immunizations against
measles, rotavirus and
cholera
• Improved water
supply and sanitation
facilities
• Promotion of personal
and domestic hygiene
Strategies
Cost/DALY
US $
Breast feeding
930
Measles vaccination
981
Rotavirus vaccination
2,478
Cholera vaccination
2,945
Rural water and
sanitation improvement
7,876
ORT
10,020
Urban water and
sanitation improvement
25,510
Strategies for
Diarrheal Disease Control
Are breastfed babies protected
against rotavirus disease?
Case-control study in rural Bangladesh
n=102 cases with clinically severe rotavirus diarrhea;
n=2587 controls
Results
• eBF of infants associated with significant protection
against severe rotavirus diarrhea; RR=0.10 [95% CI:
0.03,0.34]
• NoBreastfeeding
overall protection
BF control
during the
is stillassociated
importantwith
for the
of
first
2 yearsdue
of life;
RR = 2.61 [95%
CI: 0.62,11.02].
diarrhea
to non-rotaviral
enteropathogens.
BF and Risk of Rotavirus Diarrhea:
Prevention or Postponement?
Clemens J et al. Pediatrics 1993; 92:680-5.
Surveillance study in Muntinlupa (2005-2006)
evaluating the burden of RV disease
Significantly higher prevalence of RV infection
among non-BF infants <6 mos [24% vs. 15%, p=0.04]
No statistically significant difference in prevalence of
RV infection between BF and non-BF infants
(p=0.519) for children <5 yr old
BF and Risk of Rotavirus Diarrhea
Carlos CC et al. J Infect Dis 2009; 200 (Suppl 1): S174-81.
Know what you’re up against…
Utilize your resources well...
Keep the beast at bay…
Taming the Beast: Diarrhea